© 2015



If you read the ingredients of some vitamin supplements, you will probably see the word "cholecalciferol".

Cholecalciferol is another name for Vitamin D3, the most familar form of Vitamin D.

In your bloodstream, D3 is transported first to the liver, where it is converted to "25-OH-D3".  This compound then goes to your kidneys for another conversion.  The product, known as "calcitriol", is considered the most active form of Vitamin D.

That doesn't tell us much about Vitamin D, though. 

What does it do?  Should you take supplements?  Under what conditions? 

Most people know by now that if you go in the sun, it makes Vitamin D in your skin. 

And most of us know that sometimes, it's not practical to get all your Vitamin D from sunlight. 

When it's bitter cold and windy, who really wants to go outside and try to bask in the winter sunlight?  And besides, it is often cloudy in the winter anyway.

I used to think Vitamin D was one of the most boring pathways in biochemistry.  I never had much interest in it, but that was a function of the curriculum.  Mainstream thinking for a long time was that vitamins really don't do much, other than prevent deficiency.  I was taught this idea, as many still are.

However, that idea is becoming obsolete.

Little did I know that Vitamin D actually does much more than "preventing deficiency".  It helps to keep us healthy in a number of ways.

Because it does so much, there are some things you should know about Vitamin D.  As we'll see, it may not be as simple as taking some pills and moving on to something else.

A Quick Note

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In This Article

Vitamin D and Cholesterol

Vitamin D and Serotonin

Vitamin D Sulfate

Vitamin D Toxicity

Vitamin K2

How Much Vitamin D?


Vitamin D and Cholesterol

Vitamin D and cholesterol synthesis are very closely connected. 

In fact, without cholesterol, your cells could not make Vitamin D

The last step in cholesterol biosynthesis is the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol. 

To make Vitamin D3, some of the 7-DHC is instead converted to cholecalciferol (D3).   Thus, 7-DHC is also known as Provitamin D.

That conversion happens in the upper layer of skin, known as the epidermis.  The epidermis actually has five distinct layers.  Current thinking is that most of the Vitamin D synthesis occurs in the third and fourth layers down.  These are the stratum granulosum and stratum spinosum, in case you're curious.  (I seem to recall that some studies also show Vitamin D production on the surface of the skin, as if oils are carrying some of it.)

Either way, the energy source is primarily UVB from the sun, with UVA having a lesser contribution.

The reactions occur in a zone that's a fraction of a millimeter thick.  Sometimes it is even less than one-tenth of a millimeter. 

Once made, some of the Vitamin D3 is converted to calcitriol, right there in the skin, where it is used by the skin cells.

Remember that calcitriol is the most biologically-active form of Vitamin D.

So, what does it do there in the skin?

Among other things....  it suppresses tumors

That's right:  Vitamin D is necessary to keep our skin cells from growing out of control.  And in fact, without that Vitamin D, the sun's light would be much more harmful.  Together with DNA repair mechanisms, Vitamin D represents an important line of defense against skin cancer.

Vitamin D actually performs a number of vital functions.  For one, it has been found to reduce inflammation in the intestinal lining;  as we all know, digestive diseases have become unfortunately very common.  While Vitamin D deficiency is far from being the only cause, it is probably a contributing factor in many cases.  Think of how many people work indoors all day.  They go to the office before it's even light, and they get home after it's dark.  The most light they get is from artificial fixtures that provide virtually no Vitamin D.

In fact, Vitamin D deficiency has been linked to everything from asthma to rheumatoid arthritis.  Likewise, cholesterol is vitally important.  Without sufficient cholesterol, a number of vital processes simply cannot occur.   In other words, lowering your cholesterol could actually be a bad thing.

Your body has a couple of fail-safe mechanisms to try to ensure a supply of cholesterol.   Even so, that doesn't guarantee a supply of Vitamin D, especially in the winter.  That's because the key step requires UV from the sun.  So, you can have sufficient cholesterol while not having enough Vitamin D. 

Vitamin D and Serotonin

Science is showing that Vitamin D is necessary for maintaining healthy serotonin levels.   And you may know that serotonin is important for a sense of well-being.

That said, there are people out there who are going to need more than just a Vitamin D pill.  Because the serotonin system is so complex, Vitamin D is just a part of it.  In other words, I wouldn't suggest relying on Vitamin D alone;  for some people, that would probably be counter-productive.

Just know that a lack of Vitamin D is probably going to make an existing problem worse.

I have occasionally met people who got plenty of sunlight, yet there were strong indications they had low serotonin.  It is unlikely that they had a Vitamin D shortage, being out in the sun all day, every day.  (Recently I saw a literature reference to high sunlight / low serotonin individuals... just have to find it and put a note here.)

Recently, Vitamin D has been found to regulate serotonin synthesis via gene activation.  Switching genes "on" or "off" is an enormous part of human health.  Human beings (as well as plants and animals) have many genes that are dormant until something activates them.  Even more remarkable is that science is beginning to find "genes within genes".  

Now, as for the serotonin: 

Vitamin D activates a gene that codes for an enzyme known as tryptophan hydroxylase 2 (a.k.a. "TPH2").  This happens in your brain.   Once TPH2 is made, it converts tryptophan to 5-hydroxytryptophan (5-HTP).   Then, another enzyme converts the 5-hydroxytryptophan to 5-hydroxytryptamine, also known as serotonin. 

For this pathway to be useful, you need a supply of Vitamin D and a supply of tryptophan.  Then, that tryptophan has to get routed into the serotonin pathway.  5-HTP goes directly there;  tryptophan can be used for a number of other things instead.

A little digression here.  Maybe one reason why pizza makes us happy is that mozzarella cheese is very high in tryptophan.   (Other rich sources of tryptophan include walnuts, tofu, turkey, and lentils.)

Incidentally, serotonin may be a reason why so many people crave chocolate (and cheese).

Both foods tend to elevate serotonin levels.  Both can also elevate dopamine levels.  As I understand it, though, overconsumption can actually decrease these neurotransmitters, by activating production of enzymes that break them down. 

Perhaps it is your body's way of telling you:  "Hey, easy on the chocolate and cheese there!  Now go and get some leafy green vegetables!"

(Incidentally, Vitamin D deficiency has also been linked to that dread disease which involves a lack of dopamine... Parkinson's.)

As I said, there are people out there who may have imbalances that foods and Vitamin D alone cannot address.  Some people may have organic conditions that reduce overall serotonin synthesis.    And finally, serotonin is not the only neurotransmitter;  I earlier mentioned dopamine, but there are others, too:  norepinephrine, GABA, and so on.  According to science, human mood is the result of a complex interplay between the various neurotransmitters.

Here's the overall point of this section:  Vitamin D may not be a cure-all for feeling bad... but a Vitamin D deficiency will make things worse.

Vitamin D Sulfate

There is plenty of evidence that Vitamin D sulfate exists;  the question is, what does it do? 

There was a rash of studies in the 1980's, but then the research sort of tapered off.  One or two of the studies claimed that Vitamin D sulfate had no biological activity, but they were making an assumption.  They assumed Vitamin D sulfate would have to have the same activity as regular Vitamin D.   So they checked for calcium- and phosphate-regulating activity, and they found very little.

The thing is, if your cells are making two different molecules, chances are those molecules will do two different things.  Our biochemistry doesn't just randomly stick functional groups on molecules for no reason.  Generally, it is to change the function, or else to change the solubility (which usually changes the function).   There can be overlap in function, but it's not going to be 100% overlap.

Vitamin D sulfate is known to circulate in the bloodstream of humans, and it has been found in the milk of humans and lab animals. 

There are ideas about its purpose, but not a lot of definite answers yet.  It might have something to do with regulating the usable Vitamin D that you get from sunlight. 

Whatever the case may be, it's been proven that sunlight has more benefits than Vitamin D alone would explain.

In other words, if you can get your Vitamin D from sunlight, that's the best solution.

Vitamin D Toxicity

Water-soluble vitamins are generally non-toxic;  for example, Vitamin C can be taken in doses of thousands of milligrams.

Vitamin D is special, though, because it's fat soluble, and it's technically more of a steroid than a vitamin.

Vitamin D regulates calcium mobilization from your bones.  Thus, too much Vitamin D could actually be lethal.  In fact, cholecalciferol (Vitamin D3) is used as a rodent poison because of this.  Don't panic just yet, though;  in humans, serious toxicity probably won't start to occur until well above 20,000 International Units (IU).  

In fact, many people have been given doses of 100,000 IU or more with no signs of acute toxicity.  That's not a dose I'd want to take every day, but once in a great while it's probably OK, especially if you make sure to get the right nutrients along with it (more about that later.) 

I can think of four major reservations with Vitamin D pills or drops.

One, the useful dose is down in the tens of micrograms.  2,000 IU of D3 is only 50 micrograms.  Manufacturing can be tricky, because it is not easy to measure out 50 micrograms of something.  Variability becomes a problem.  To avoid this, I would try to get a brand that's made to U.S.P. standards.  (U.S.P. stands for United States Pharmacopeia.)

Second, D3 is fat-soluble.  It has been shown to build up quickly in the fat cells, and it doesn't leave for a long time.  That means if you suddenly lose a lot of weight, you could experience Vitamin D toxicity when it all mobilizes rapidly.  This could lead to kidney stones and other unpleasantries, up to and including death.   So, Vitamin D is something I would be careful not to take in excess. 

Third, make sure it's D3, not D2.  Vitamin D2 is not as effective as D3 and could have even more toxicity issues.  Actually, know what?  If you want to know if D2 is any good, ask vegans who have been using it for a long time.  I'm going to leave that one alone, mostly, except to say that D3 is the one that we make from sunlight.  

Fourth, and probably most important:  make sure you're getting Vitamin A, magnesium, and especially Vitamin K2 when taking D supplements.

Vitamin K2

For many years, we were taught that Vitamin K was practically a footnote in the science of vitamins.  It was for blood clotting, and that was all;  nothing more to see here. 

Actually, "Vitamin K" is three different vitamins, each with different properties and functions.  And one of them-- Vitamin K2-- is emerging as very important if you're taking Vitamin D supplements.   K2, which unlike K1 is a group of similar compounds, was actually known for decades.  However, it was assumed to be involved only in clotting.

Because K2 is really a group of compounds, they don't all have exactly the same activity.  There is some overlap in function, though.  (For this article I'm just going to treat them as one compound, "Vitamin K2".)

Vitamin K2, like many vitamins, is a cofactor.   That means it is required for a certain proteins or enzymes to function.  With Vitamin K2, one of these proteins is "Matrix Gla Protein", or MGP.  The protein actually helps prevent calcification of arteries.  

MGP, as well as another protein called osteocalcin, also inhibits the calcification of soft tissues. 

You might be surprised to know that calcium in your blood is at or above the natural limit of saturation.  The word for that is "supersaturated".  For example, see this paper. 

What does that mean?

It means calcium can start precipitating from your blood very easily.   And because the calcium is in the form of "carbonate hydroxyapatite", that means the precipitate will be the same stuff that your bones are made of. 

And that means.... bone spurs, calcified arteries, and calcified soft tissues.

Vitamin K2 activates proteins that protect you against that.  Without them, you would not even be able to survive.  Anything that increased your calcium levels would cause dangerous buildup in your kidneys, heart, coronary arteries, brain, and a bunch of other places. 

And Vitamin D increases your calcium levels. 

Now I think you can understand the importance of Vitamin K2.  

This was only a fairly brief look at Vitamin K2 and its connection to the Vitamin D system.  Get a good book on the subject, such as this one, to learn more about it.  This is one subject that's definitely worth it.  If you take Vitamin D supplements, and many people do, then you need to read up on this!

How Much Vitamin D?

The best way to answer this question, probably, is to say "Get your levels checked".  Even that is not a perfect answer, because there are still a lot of variables.  One person's Vitamin D requirements could be higher or lower than someone else's.

And let us not forget the requirement for Vitamin K-2, Vitamin A, and magnesium. 

Current thinking seems to be that if your D levels are between 30 and 70 nanograms per milliliter, you're in good shape.   That figure could change.  I can think of at least one scientific reason why levels can be misleading, but I suppose levels are the best we have at the moment.

Now, what about Vitamin D pills?

Several countries have set a recommended intake somewhere between 400 and 800 IU.  The "safe upper limits" are currently set at 2,000 to 4,000 IU as far as I can ascertain.  These seem to be fairly rational values.  Assuming enough Vitamin K2 in the diet, most people could take these doses every day, indefinitely, and probably not get any side effects. 

Except, that is, for the fat-storage problem. 

What would happen if something caused you to lose fifty pounds after you'd been taking a few thousand IU's of D3 every day?  

This goes back to that whole problem of "supersaturated calcium".  Sudden mobilization of D3 from fat cells could be dangerous.

For some people, Vitamin D could cause problems even before that.  Some people have had complications from just 2,000 IU a day.   Symptoms included sore joints in the fingers, toes, and knees.  I know of one person who had joint pains and restricted movement after taking 2,000 IU of D3 but was able to get rid of the pains within half an hour by eating a food known to be rich in Vitamin K2.  

Lack of K2 is not the only concern with Vitamin D supplements.  As mentioned earlier, there are probably aspects of the Vitamin D system that we're not getting unless we go in the sun.  

Vitamin D supplements are most useful for the winter months, especially in the northern latitudes where there's really not much UVB reaching the ground.   Outside of that, I would prefer to be going out in the sunlight for twenty minutes a day, in the middle of the day. 

It's worth mentioning that I've known people who spent much time in the sun and still ended up with bone spurs.  However, it's possible they were not getting much K2, A, or magnesium.  And I'm fairly sure they were not going out of their way to get these nutrients.

People with more melanin in their skin make less Vitamin D.  That means they're even more likely to become Vitamin D deficient when living in the Northern latitudes.  This is an area where (again) supplements are probably going to be the easiest, quickest solution. 


Vitamin D supplements have proven benefits, but they also have some unique risks.  That's mainly because of the calcium modulating properties.

The maximal safe intake is not going to be the same for everyone.  For most people, 2,000 to 4,000 IU is well within the safe range, as long as you're getting enough Vitamin A, Vitamin K2, and magnesium at the same time.

If you haven't been taking Vitamin D in a while, it might be a good idea to "ramp up" the dose, starting low (say, 400 IU) and progressing up to whatever will bring your Vitamin D levels into the recommended range.

One-time doses of Vitamin D can go up into the tens of thousands of IU, or in rare cases even higher.  I wouldn't do this very often.  In fact, if you have calcification issues, I wouldn't do this at all until you can get that squared away.

Also remember what I said about cholecalciferol going into your fat cells.  Eventually it's going to mobilize back out of there.

Sunlight-derived Vitamin D is the safest, but still make sure you're getting the other nutrients in your diet.

If you can't get enough sunlight, supplements are the quickest and easiest way to obtain your Vitamin D.  If you find that Vitamin D gives you pain and stiffness in your fingers, toes, knees, etc, then it might be that you're not be getting enough of the co-nutrients (especially K2) that help safely handle Vitamin D.

Don't be afraid of Vitamin D supplements;  just know that they have to be taken intelligently, if you're going to take them.  That's really the bottom line.

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